Objectives: It is not known whether current use of the medication primidone affects brain gamma-aminobutyric acid (GABA) concentrations. This is an important potential confound in studies of the pathophysiology of essential tremor (ET), one of the most common neurological diseases. We compared GABA concentrations in the dentate nucleus in 6 ET patients taking primidone vs. 26 ET patients not taking primidone.
Methods: 1H magnetic resonance spectroscopy (MRS) was performed using a 3.0 Tesla Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in two cerebellar volumes of interest (left and right) that included the dentate nucleus.
Results: The right dentate GABA concentration was similar in the two groups (2.21 ± 0.46 [on primidone] vs. 1.93 ± 0.39 [not on primidone], p=0.15), as was the left dentate GABA concentration (1.61 ± 0.35 [on primidone] vs. 1.67 ± 0.34 [not on primidone], p=0.72). The daily primidone dose was not associated with either right or left dentate GABA concentrations (respective p = 0.89 and 0.76).
Conclusions: We did not find a difference in dentate GABA concentrations between 6 ET cases taking daily primidone and 26 ET cases not taking primidone. Furthermore, there was no association between daily primidone dose and dentate GABA concentration. These data suggest that it is not necessary to exclude ET patients on primidone from MRS studies of dentate GABA concentration and, if assessment of these concentrations were to be developed as a biomarker for ET, primidone usage would not confound interpretation of the results.

Absorption, Distribution and Excretion
The bioavailability of primidone via oral administration is up to 80%, with a time to peak concentration (Tmax) of 2–4 hours. After oral administration of 500 mg primidone, the peak plasma concentration (Cmax) is 2.7 ± 0.4 μg/mL, with a time to peak concentration of 0.5–7 hours. AUC data for primidone are not yet available. The urinary recovery rate of primidone is 72.9–80.6%. The volume of distribution of primidone is 0.5–0.8 L/kg. The clearance rate of primidone is 30 mL/min. Mice were administered a teratogenic dose of primidone (100 mg/kg) via gastric tube at three different time points during pregnancy: days 6–14, days 12–14, and day 14 only. Blood samples were collected at 1, 4, 8, and 24 hours post-administration on day 14. Concentrations of primidone and its metabolites phenylethylmalonamide (PEMA) and phenobarbital were determined by gas chromatography. No accumulation of parent compounds or metabolites was observed after repeated dosing; each substance was cleared from plasma within 24 hours. The metabolic rate of primidone increased with increasing dosing time. Peak metabolite concentrations were higher in the two-dose multiple-dose group compared to the single-dose group. In the multiple-dose group, PEMA concentrations were higher than primidone concentrations for 3–8 hours before decreasing; phenobarbital showed a similar pattern, although its concentration was lower than PEMA. Researchers conducted a placental transport study of primidone and its metabolites in 14 pregnant women who received primidone (5 of whom also received phenytoin sodium, ethosuximide, or sodium valproate) for epilepsy treatment. Results showed similar concentrations of primidone, PEMA, phenobarbital, and their polar metabolites (p-hydroxyphenobarbital and p-hydroxyphenobarbital glucoside) in maternal and cord blood at delivery. Researchers investigated the pharmacokinetics of a single oral dose of 500 mg pregabalin (PRM) in 7 patients with acute viral hepatitis and 7 healthy controls. The elimination half-life and apparent clearance of unmetabolized pregabalin (PRM) in the patients were 18.0 ± 3.1 hours and 42 ± 14 mL/kg/hour (mean ± standard deviation), respectively, which were not significantly different from those in the control group (half-life 17.0 ± 2.4 hours; clearance 35 ± 8 mL/kg/hour). The metabolite phenylethylmalonamide (PEMA) was detected in the serum of all healthy subjects within 2–24 hours. In contrast, this metabolite was undetectable in the serum of all but one patient (below 2 μmol/L). Serum phenobarbital (PB) levels in all subjects were below the limit of detection (below 2 μmol/L). The results indicate that although there is evidence that the metabolism of this drug can be affected by acute viral hepatitis, pregabalin accumulation and its associated toxicities are unlikely to occur in patients with epilepsy who develop acute viral hepatitis. This article discusses the possibility and impact of impaired conversion of pulmidone to phenobarbital (PB). Pulmidone is slowly absorbed after oral administration in dogs, reaching peak plasma concentrations 2–4 hours after administration. For more complete data on the absorption, distribution, and excretion of pulmidone (11 metabolites), please visit the HSDB record page. Metabolism/Metabolites Pulmidone is metabolized to phenobarbital and phenylethylmalonamide (PEMA). This metabolism is primarily mediated by CYP2C9, CYP2C19, and CYP2E1. This study used a physiological-based pharmacokinetic model to model the parent compound pulmidone and its two metabolites, phenobarbital and phenylethylmalonamide (PEMA), to investigate the metabolic differences of pulmidone in humans, rats, and mice. This model simulated pharmacokinetic data of the parent compound and its metabolites in plasma and brain tissue from previously published independent studies in three species. The metabolism of primidone and its metabolites varied considerably among three subjects in two independent studies. Estimates of primidone metabolism, expressed as the maximum metabolic rate Vmax, showed that the rates of phenobarbital production ranged from 0 to 0.24 mg/kg/min, and the rates of PEMA production ranged from 0.003 to 0.02 mg/kg/min in the three subjects. Further model simulations indicated that rats were more efficient at generating and clearing phenobarbital and PEMA than mice. However, the overall metabolic profile of primidone and its metabolites in mice suggested a higher risk of toxicity due to the longer residence time of phenobarbital in its tissues and the carcinogenicity of phenobarbital (as indicated by long-term bioassays). ...
This study investigated placental transport of primidone and its metabolites in 14 pregnant women who received primidone (five of whom also received phenytoin sodium, ethosuximide, or sodium valproate) for epilepsy. Results showed similar concentrations of primidone, phenylethylmalonamide (PEMA), phenobarbital, and their polar metabolites (p-hydroxyphenobarbital and p-hydroxyphenobarbital glucoside) in maternal and cord blood at delivery.
This study also investigated the pharmacokinetics and metabolism of primidone at steady state in 10 elderly patients aged 70–81 years and 8 healthy controls aged 18–26 years. The half-life and clearance (mean ± standard deviation) of primidone were similar in the elderly and younger participants (12.1 ± 4.6 h vs 14.7 ± 3.5 h and 34.8 ± 9.0 mL/kg/h vs 33.2 ± 7.2 mL/kg/h, respectively). Compared to the parent drug, serum concentrations of the metabolites phenylethylmalonamide (PEMA) and phenobarbital were higher in older adults than in younger adults, with the difference in PEMA being statistically significant (P<0.01). Renal clearance of primidone, phenobarbital, and PEMA was slightly reduced in older adults, but only the reduction in PEMA was statistically significant. The proportion of unchanged primidone excreted in urine was decreased in older patients, while the proportion of PEMA excreted was increased. Aging is associated with increased PEMA accumulation, but this is unlikely to have significant clinical implications. Although phenobarbital was not detected, in 46 patients with epilepsy, long-term use of different doses of primidone following a single dose resulted in the accumulation of both phenobarbital and phenylethylmalonamide (PEMA) in serum. Despite significant inter-individual differences, the concentrations of both metabolites were positively correlated with the concentration of the parent drug, with phenobarbital concentrations consistently higher than PEMA concentrations. Two subjects took primidone (750 mg, divided doses) daily for more than 3 years. In this study, after a single 750 mg dose, peak serum concentrations of primidone were rapidly reached (within 0.5 hours) and then slowly decreased (half-lives of 5.3 hours and 7.0 hours, respectively). In both subjects, peak concentrations of the metabolites PEMA (12 μg/mL and 10 μg/mL, respectively) and phenobarbital (33 μg/mL and 11 μg/mL, respectively) remained relatively stable. In cerebrospinal fluid, the binding of PEMA and primidone to proteins was negligible, while the binding rate of phenobarbital to proteins was approximately 60%. For more complete metabolite/metabolite data on primidone (9 metabolites in total), please visit the HSDB record page. The half-life of primidone is 7–22 hours in adults, 5–11 hours in children, and 8–80 hours in neonates. This study investigated steady-state pharmacokinetics and metabolism of primidone in 10 elderly patients aged 70–81 years and 8 control subjects aged 18–26 years. The half-life and clearance values (mean ± standard deviation) of primidone were similar in the elderly and younger participants (12.1 ± 4.6 h and 14.7 ± 3.5 h, respectively, and 34.8 ± 3.5 h, respectively). The clearance values were 9.0 and 33.2 ± 7.2 mL/kg/hr, respectively. … In a study of 8 patients with epilepsy (aged 18–26 years) who received long-term primidone treatment (mean daily dose of 422 ± 115 mg), the half-life of primidone was 14.7 ± 3.5 hours. The pharmacokinetics of a single oral dose of 500 mg primidone (PRM) were investigated in 7 patients with acute viral hepatitis and 7 healthy controls. The elimination half-life and apparent clearance of unmetabolized PRM in patients were 18.0 ± 3.1 hours and 42 ± 14 mL/kg/hr (mean ± standard deviation), respectively, which were not significantly different from those in the control group (half-life 17.0 ± 2.4 hours; clearance 35 ± 8 mL/kg/hr). The serum half-lives of primidone, PEMA (phenethylamine formamide), and phenobarbital have been reported to be 1.85 hours, 7.1 hours, and 41 hours, respectively. For more complete data on the biological half-lives of primidone (a total of 6), please visit the HSDB record page.

Hepatotoxicity
In clinical trials of epilepsy, primidone treatment did not increase the incidence of elevated serum transaminases or hepatotoxicity. Primidone treatment can lead to elevated levels of gamma-glutamyl transferase (GGT). Elevated alkaline phosphatase levels are primarily caused by the bone isoenzyme of this enzyme. There are currently no conclusive reports of primidone causing hepatotoxicity in humans, nor have there been any reports of it being associated with acute liver failure. Notably, primidone appears to cause cirrhosis in dogs. Due to its structural similarity to phenytoin sodium and phenobarbital (aromatic anticonvulsants), it is suspected that it may cross-react with these drugs, leading to anticonvulsant allergy syndrome, but no conclusive case reports have been published. Probability Score: E (Unproven, but suspected as a rare cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is substantial evidence that primidone use during lactation may affect breastfed infants. Infant serum concentrations of primidone and its metabolites are usually near or within the therapeutic range, and there are reports of sedation and feeding difficulties in infants. On the other hand, infants exposed to primidone in utero sometimes experience withdrawal symptoms, which may be relieved by breastfeeding or worsened by abrupt cessation of breastfeeding. If the mother needs to take primidone, this is not a reason to stop breastfeeding. However, infant sedation, feeding difficulties, slow weight gain, and developmental milestones must be monitored, especially in younger exclusively breastfed infants and those using multiple antiepileptic drugs. If there are concerns about toxicity, measuring the infant's serum drug concentration may help rule out toxicity.
◉ Effects on Breastfed Infants
An infant died from asphyxiation after being suffocated by parents suffocating in their sleep. The sedative effects of primidone, phenobarbital, and phenytoin sodium in breast milk may have been a contributing factor to the death. Autopsy revealed phenobarbital in the infant's serum (8 mg/L) and liver (16 mcg/g).
A mother with epilepsy took 250 mg of primidone and 2.4 g of valproic acid three times daily during pregnancy and postpartum. Her breastfed infant experienced sedation in the second week postpartum. The drowsiness disappeared after breastfeeding was discontinued. The drowsiness was likely caused by primidone in the breast milk.
A woman who took 1 g of primidone and 1 g of carbamazepine daily during pregnancy and postpartum breastfed her infant for 5 weeks; no difference in the infant's activity level before and after breastfeeding was observed.
A newborn presented with suspected drug-induced drowsiness; the mother took primidone, carbamazepine, and phenytoin sodium (dosage not specified). Breastfeeding was discontinued 30 days after birth due to drowsiness after each feeding and poor weight gain. These authors also found that 15 infants whose mothers were taking antiepileptic drugs (including primidone) and were partially breastfed had slower weight gain in the first 5 days postpartum than infants born to 75 infants born to mothers with epilepsy who were bottle-fed or to a control group of mothers who did not take any medication. A four-day-old infant presented with potentially drug-related drowsiness, pallor, and feeding difficulties. The mother had been taking primidone 625 mg, phenobarbital 100 mg, phenytoin sodium 200 mg, and sulfodiazide 200 mg daily during pregnancy and postpartum. The infant required nasogastric feeding for five weeks, during which partial breastfeeding continued. In a cohort study of women who took primidone during pregnancy and their infants, seven infants experienced withdrawal symptoms after birth. One infant was partially breastfed, while the others were not. In contrast, five breastfed infants did not experience withdrawal symptoms. A mother who took primidone 11.4 mg/kg, valproic acid 13.6 mg/kg, and ethosuximide 11.4 mg/kg daily during pregnancy and postpartum experienced sedation lasting for five weeks after birth in her exclusively breastfed infant, with slow weight gain in the first four weeks. This reaction was likely caused by primidone in breast milk.
A mother with epilepsy was taking 250 mg of primidone twice daily while breastfeeding. When her dose was doubled to 500 mg twice daily, the decrease in breastfeeding frequency was thought to be due to the drug passing into breast milk.
A mother was taking 375 mg of primidone, 90 mg of phenobarbital, and 800 mg of carbamazepine daily. Despite a phenobarbital concentration of 3.4 mg/L in saliva, her breastfed infant was doing well. At 7 months of age, after the mother abruptly stopped breastfeeding, the infant experienced multiple startle reactions and infantile seizures, confirmed by an abnormal electroencephalogram (EEG). After 15 months of continued phenobarbital use, the infant's seizures were controlled and remained seizure-free until age 5.
A woman with long-term epilepsy became pregnant while taking primidone and levetiracetam. During pregnancy, her medication dosage was reduced to maintain a serum primidone (phenobarbital) concentration of 3.4 mg/L and a levetiracetam serum concentration of 40.5 mg/L. The doctor instructed the mother to stop breastfeeding after 3 days. The next day, her baby experienced withdrawal seizures. After breastfeeding was resumed, the baby's seizures stopped and did not recur. At 6 months of age, all the baby's test results were normal, growth and development were good, and there were no seizures.
◉ Effects on breastfeeding and breast milk
Currently, there is no direct effect, but mothers taking antiepileptic drugs stop breastfeeding earlier than mothers not taking antiepileptic drugs and need to supplement with more formula. Most of these reports come from earlier studies that used sedatives such as phenobarbital and primidone. Infant sucking difficulties and sedation are reasons for reduced breastfeeding.
Protein binding
Primidone has a protein binding rate of 10.78-13.70% in serum.

Clin Neuropharmacol.2016Jan-Feb;39(1):24-8; Wikipedia.

According to data from the National Toxicology Program (NTP), primidone may be carcinogenic. Primidone is an odorless, white crystalline powder with a slightly bitter taste and no acidity. (NTP, 1992) Primidone is a pyrimidinone compound with the structure dihydropyrimidine-4,6(1H,5H)-dione, substituted with ethyl and phenyl groups at the 5-position. It is used as an anticonvulsant to treat various types of epileptic seizures. It is both an environmental pollutant and an exogenous substance, and also has anticonvulsant effects. Primidone is an anticonvulsant used to treat essential tremor, as well as grand mal seizures, psychomotor seizures, and focal seizures. Primidone was developed by J. Yule Bogue and H.C. Carrington in 1949 and approved by the U.S. Food and Drug Administration (FDA) on March 8, 1954. Primidone is an antiepileptic drug. Its physiological action is achieved by reducing disordered electrical activity in the central nervous system. Primidone is an aromatic anticonvulsant used to treat complex, partial, and generalized epilepsy. Primidone treatment may cause elevated gamma-glutamyl transferase levels, but not elevated serum transaminases. Although primidone's structure is similar to phenobarbital and phenytoin sodium, there have been no reports of clinically significant liver damage caused by primidone, and even if it occurs, it is extremely rare. Primidone is an analogue of phenobarbital and has antiepileptic effects. Although its mechanism of action is not fully elucidated, primidone may act similarly to phenobarbital by activating the gamma-aminobutyric acid (GABA) A receptor/chloride channel complex, thereby prolonging the opening time and increasing the opening frequency of chloride channels within the receptor complex. This leads to altered electrical activity of nerve cell membranes, causing hyperpolarization and preventing partial and tonic-clonic seizures. Furthermore, the drug is partially metabolized to phenobarbital and phenylethylmalonamide (PEMA), which may also contribute to its antiepileptic effect.
Primidone is a barbiturate derivative that can be used as a GABA modulator and antiepileptic drug. Primidone is partially metabolized in the body to phenobarbital, and some of its efficacy is attributed to this metabolite.
Drug Indications
Primidone is commonly used to treat generalized tonic-clonic seizures, psychomotor seizures, and focal seizures. It has also been investigated and used to treat essential tremor.
FDA Label
Mechanism of Action
Primidone and its metabolites phenobarbital and phenylethylmalonamide (PEMA) are all active anticonvulsants. Primidone does not directly interact with GABA-A receptors or chloride channels, unlike phenobarbital. Primidone reduces the frequency of nerve discharges by altering the transport of transmembrane sodium and calcium ion channels, which may explain its effects on seizures and essential tremor.
The transient receptor potential (TRP) channel TRPM3, associated with melanocyte-inhibinine, is a non-selective cation channel expressed in nociceptive neurons and can be thermally activated. Since TRPM3-deficient mice exhibit inflammatory thermal hyperalgesia, pharmacological inhibition of TRPM3 may have analgesic effects. This study used a fluorescence calcium ion influx assay and a compound library containing approved or clinically tested drugs to screen TRPM3 inhibitors. The biophysical properties of the channel inhibition were evaluated using electrophysiological methods. The nonsteroidal anti-inflammatory drug diclofenac, the tetracyclic antidepressant maprotiline, and the anticonvulsant primidone were shown to be highly potent TRPM3 blockers, with half-maximal inhibitory concentrations (IC50) ranging from 0.6 to 6 μM, and exhibiting significant specificity for TRPM3. Notably, primidone inhibited pregnenolone sulfate (PregS) and heat-induced TRPM3 activation at concentrations far below those commonly used in antiepileptic therapy. Primidone blocked PregS-induced Cai influx through TRPM3 via allosteric regulation and reversibly inhibited the atypical inward rectifying TRPM3 current induced by the combined action of PregS and clotrimazole. In vivo experiments have shown that low-dose primidone has analgesic effects in mice, using PregS and heat-induced pain models, including an inflammatory hyperalgesia model. Therefore, applying approved drugs at concentrations below those required to induce anticonvulsant effects provides a shortcut for studying the physiological and pathophysiological effects of TRPM3 in vivo.

C12H14N2O2

218.25

218.106

125-33-7

Primidone-d5;73738-06-4

4909

White to off-white solid powder

1.138g/cm3

520.7ºC at 760mmHg

281-282°C

228.2ºC

6.08E-11mmHg at 25°C

1.528

1.195

2

2

2

16

279

0

DQMZLTXERSFNPB-UHFFFAOYSA-N

InChI=1S/C12H14N2O2/c1-2-12(9-6-4-3-5-7-9)10(15)13-8-14-11(12)16/h3-7H,2,8H2,1H3,(H,13,15)(H,14,16)

5-ethyl-5-phenyl-1,3-diazinane-4,6-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (11.45 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (11.45 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (11.45 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)